The long-term goal of this project is to define how thiazolidinediones (TZDs) and other ligands for the peroxisome proliferator activated receptor gamma (PPARg) could be used clinically to treat patients with prostate cancer. Although PPARg ligands have been shown to reduce proliferation of human prostate cancer cells in vitro and inhibit prostate tumor growth in vivo, the mechanisms by which these reductions in proliferation and tumor growth occur are not fully understood. As a result, it is difficult to determine which patients would benefit from treatment regimens involving PPARg ligands. It is my hypothesis that TZDs and other PPARg ligands reduce prostate cancer cell proliferation by inhibiting the function of the androgen receptor (AR) as well as by inducing AR-independent alterations in gene expression. The experiments in this proposal are designed to test this hypothesis by examining the effects of TZDs such as ciglitazone on human prostate cancer cell lines both in vitro and in vivo. In Aim 1, we will define the mechanisms by PPARg ligands inhibit AR function in human prostate cancer cell lines. In this studies we will examine not only the effects of TZDs on androgen-induced gene expression but also the ability of TZDs to regulate the assembly of AR transcriptional complexes on chromatin. In Aim 2, we will test the hypothesis that PPARg ligands inhibit prostate cancer cell proliferation by altering expression of proteins that regulate cell cycle progression. To accomplish this aim, we will determine the importance of cyclin D1 down-regulation in TZDinduced decreases in cell proliferation. In addition we will explore whether TZDs induce expression of cyclin dependent kinase inhibitors and define the role of this up-regulation in the TZD anti-proliferative effect. In Aim 3, we will use an athymic mouse xenograft model to determine whether combination treatments involving PPARg ligands and vitamin D receptor agonists are effective at reducing growth of human prostate tumors in vivo. The data obtained from these studies will provide us with new information regarding the signaling pathways activated by PPARg ligands within human prostate cancer cells. In addition, these data will demonstrate how PPARg ligands can be used alone or in combination with other drugs to treat prostate cancer. This information can then be used to design prostate cancer treatments involving PPARg ligands that can be tested initially in animal models and then further explored in clinical trials.

K01CA114253

2006-07-01

2012-06-30